Thursday, January 17, 2013 @6:23 AM
Why does MSUD affect growth of the brain?
So, after reading the research article, why does MSUD affect the brain? First of all, in MSUD, since branched-chain alpha-ketoacid dehydrogenase is deficient, isoleucine, valine and mainly leucine cannot be broken down. Leucine will then accumulate in the brain and blood. Accumulation of branched-chain amino acid especially leucine, was found to inhibit the transport of other essential amino acids such as threonine, trytophan and tyrosine since they share the same transporter for brain access. Hence, the brain will lack these essential amino acids and paired with improper protein synthesis due to the disease, brain growth will be affected. Another proposed problem is that the accumulation of branched-chain ketoacid will inhibit the Krebs cycle and decrease energy production. ATP depletion will then lead to Na+/K+ ATPase failure and cell swelling.
A solution to leucine, MAYBE!
From the research article, it seems that scientists may have found an alternative to leucine, which is its isomer, norleucine. Apparently, this isomer competes with leucine for access to the brain. A diet with norleucine can actually increase the survival rate of the tested mice. In addition, norleucine might also inhibit branched-chain transaminase. In MSUD, there is a hypothesis that branched-chain ketoacid accumulation in neurons may induce formation of leucine and alpha-ketoglutamate over glutamate. A high alpha-ketoglutamate/glutamate ratio can disrupt mitochondrial glutamate, aspartate, malate and αKG transport resulting in Krebs cycle failure. Krebs cycle failure will then affect the growth of the brain as stated above. All in all, norleucine might be a solution to prevent leucine deficiency in the patient's diet!
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2668944/
http://www.molbiolcell.org/content/11/5/1919.full